5-methyl-1-(naphthalen-2-yl)-1H-pyrazole derivatives and their use in potentiating the effect of opioid analgesics

ABSTRACT

The invention relates to pyrazole derivatives of formula I having pharmacological activity 
                         
and to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy and/or prophylaxis of pain.

RELATED APPLICATIONS

This application is a §371 national stage of PCT InternationalApplication No. PCT/EP2011/071583, filed Dec. 2, 2011, claiming priorityof European Patent Application No. EP10382326.6, filed Dec. 3, 2010, thecontents of each of which are hereby incorporated by reference into thisapplication.

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacologicalactivity, and more particularly to some pyrazole derivatives, toprocesses of preparation of such compounds, to pharmaceuticalcompositions comprising them, and to their use in therapy and/orprophylaxis of pain as well as their use in potentiating the analgesiceffect of opioids and opiates.

BACKGROUND

The treatment of pain conditions is of great importance in medicine.There is currently a world-wide need for additional pain therapy. Thepressing requirement for a specific treatment of pain conditions isdocumented in the large number of scientific works that have appearedrecently in the field of applied analgesics.

PAIN is defined by the International Association for the Study of Pain(IASP) as “an unpleasant sensory and emotional experience associatedwith actual or potential tissue damage, or described in terms of suchdamage” (IASP, Classification of chronic pain, 2^(nd) Edition, IASPPress (2002), 210). Although it is a complex process influenced by bothphysiological and psychological factors and is always subjective, itscauses or syndromes can be classified. Pain can be classified based ontemporal, aetiological or physiological criteria. When pain isclassified by time, it can be acute or chronic. Aetiologicalclassifications of pain are malignant or non-malignant. A thirdclassification is physiological, which includes nociceptive pain(results from detection by specialized transducers in tissues attachedto A-delta and C-fibres), that can be divided into somatic and visceraltypes of pain, and neuropathic pain (results from irritation or damageto the nervous system), that can be divided into peripheral and centralneuropathic pain. Pain is a normal physiological reaction of thesomatosensory system to noxious stimulation which alerts the individualto actual or potential tissue damage. It serves a protective function ofinforming us of injury or disease, and usually remits when healing iscomplete or the condition is cured. However, pain may result from apathological state characterized by one or more of the following: painin the absence of a noxious stimulus (spontaneous pain), increasedduration of response to brief stimulation (ongoing pain or hyperpathia),reduced pain threshold (allodynia), increased responsiveness tosuprathreshold stimulation (hyperalgesia), spread of pain andhyperalgesia to uninjured tissue (referred pain and secondaryhyperalgesia), and abnormal sensations (e.g., dysesthesia, paresthesia).

WO2006021462 and WO2007098953 describe pyrazole-containing compoundsuseful in the therapy of pain, in general, and, more particularly, intreatment of neuropathic pain or allodynia. These compounds have thefollowing chemical structure:

On another front, opioids and opiates are potent analgesics widely usedin clinical practice. Opiates refer to alkaloids extracted from poppypods (Opium Poppy; Papaver Somniferum) and their semi-syntheticcounterparts which bind to the opioid receptors. Basically to be calledan opiate one has to either be a natural opioid receptor agonist orstart the refining process with one of the natural alkaloid molecules.Once chemically altered, such as the process of converting morphine intoheroin, the drug is then labeled as a semi-synthetic opiate orsemi-synthetic opioid—the terms can be used interchangeably.Semi-synthetic opiates (or semi-synthetic opioids) include heroin(diamorphine), oxycodone, hydrocodone, dihydrocodiene, hydromorphone,oxymorphone, buprenorphine and etorphine. In contrast, opioid is ablanket term used for any drug which binds to the opioid receptors.Opioids include all of the opiates as well as any synthesized drug thatbind to opioid receptors. Synthetic opioids include methadone,pethidine, fentanyl, alfentanil, sufentanil, remifentanil, carfentanyl,tramadol, tapentadol and loperamide.

Opioid analgesics are recommended for the management of moderate tosevere pain including that which occurs following surgery and trauma andin many patients with cancer.

In spite of this background, there is still a need in the art to providealternative compounds useful in the therapy of pain, in general, andmore particularly, in the treatment of neuropathic pain or allodynia.Likewise, it would be highly desirable to dispose of new compounds whichpotentiate the analgesic effect of opioids and opiates.

BRIEF DESCRIPTION OF THE INVENTION

The inventors of the present invention have surprisingly found a familyof pyrazole derivatives which are particularly effective in the therapyof pain. Further, they have demonstrated that the administration ofthese new compounds in conjunction with an opioid or opiate maysurprisingly potentiate synergistically the analgesic effects of thelatter.

Therefore, one aspect of the invention relates to compounds having theformula (I):

wherein

-   -   R¹ and R² are independently selected from the group consisting        of substituted or unsubstituted C₁₋₆alkyl, halogen, hydroxy and        C₁₋₆alkoxy;    -   n and m are independently selected from 0, 1, and 2;    -   the dashed line (represented by - - - - - ) represents an        optional double bond or a pharmaceutically acceptable salt,        isomer, prodrug or solvate thereof.

Another aspect of this invention refers to processes for the preparationof a compound of formula (I) as defined above or a pharmaceuticallyacceptable salt, isomer, prodrug or solvate thereof.

Another aspect of this invention refers to a medicament orpharmaceutical composition comprising at least one compound of formula(I) as defined above, or a pharmaceutically acceptable salt, isomer,prodrug or solvate thereof and a pharmaceutically acceptable carrier,adjuvant or vehicle.

Another aspect of this invention refers to a compound of formula (I) asdefined above, or a pharmaceutically acceptable salt, isomer, prodrug orsolvate thereof, for use as a medicament, particularly for theprevention and/or treatment of pain.

Another aspect of this invention refers to a combination forsimultaneous, separate or sequential administration comprising at leastone compound of formula (I) as defined above, or a pharmaceuticallyacceptable salt, isomer, prodrug or solvate thereof, and at least oneopioid or opiate, for use in the prevention and/or treatment of pain.

Another aspect of this invention refers to the use of a compound offormula (I) or a combination as defined above in the manufacture of amedicament for the prevention and/or treatment of pain.

Another aspect of the present invention refers to a method for thetreatment and/or prophylaxis of pain, the method comprisingadministering to the subject in need of such a treatment or prophylaxisa therapeutically effective amount of a compound of formula (I) or acombination as defined above.

Another aspect of the present invention refers to a compound of formula(I) as defined above, or a pharmaceutically acceptable salt, isomer,prodrug or solvate thereof, for use in potentiating the analgesiceffects of an opioid or opiate.

Another aspect of the present invention refers to the use of a compoundof formula (I) as defined above, or a pharmaceutically acceptable salt,isomer, prodrug or solvate thereof for manufacturing a medicament forpotentiating the analgesic effects of an opioid or opiate.

These aspects and preferred embodiments thereof are additionally alsodefined in the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Test protocol for all tests with von Frey filaments.

FIG. 2: Chronic analgesia test of Example n^(o) 1 versus Capsaicin(acute test).

FIG. 3: Potentiation of morphine analgesia by Example n^(o) 1 in thetail-flick test in mice. Coadministration of different doses of Examplen^(o) 1 (5-20 mg/kg, i.p.) with a fixed dose of morphine (2 mg/kg, s.c.)dose-dependently increased the analgesic efficacy of morphine. Eachsymbol is the mean of percentages of analgesia±S.E.M. (N=8−12mice/group). p<0.05, **p<0.01, ***p<0.001 “Example n^(o) 1+morphine” vs.“Example no 1+vehicle” groups (Bonferroni Multiple comparison Testpost-ANOVA).

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, the following terms have themeaning detailed below.

As used herein C₁₋₆alkyl, as a group or part of a group, definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, pentyl, hexyl, and 2-methylbutyl. Likewise, C₁₋₄alkyl, as agroup or part of a group, defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms. Alkyl radicals maybe optionally substituted by one or more substituents such as a aryl,halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl,amino, nitro, mercapto, alkylthio, etc. If substituted by aryl we havean “Aralkyl” radical, such as benzyl and phenethyl.

The term C₁₋₆alkoxy means C₁₋₆alkyloxy or a C₁₋₆alkyl ether radical,wherein the term C₁₋₆alkyl is as defined above. Likewise, the termC₁₋₄alkoxy means C₁₋₄alkyloxy or a C₁₋₄alkyl ether radical, wherein theterm C₁₋₄alkyl is as defined above. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, and hexanoxy.

“Halogen”, “halo” or “hal” refer to bromo, chloro, iodo or fluoro.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable.

Radicals used in the definitions of any variable herein include allpossible isomers unless otherwise indicated.

The term “salt” must be understood as any form of an active compoundused in accordance with this invention in which said compound is inionic form or is charged and coupled to a counter-ion (a cation oranion) or is in solution. This definition also includes quaternaryammonium salts and complexes of the active molecule with other moleculesand ions, particularly, complexes formed via ionic interactions. Thedefinition includes in particular physiologically acceptable salts; thisterm must be understood as equivalent to “pharmacologically acceptablesalts” or “pharmaceutically acceptable salts”.

The term “pharmaceutically acceptable salts” in the context of thisinvention means any salt that is tolerated physiologically (normallymeaning that it is not toxic, particularly, as a result of thecounter-ion) when used in an appropriate manner for a treatment, appliedor used, particularly, in humans and/or mammals. These physiologicallyacceptable salts may be formed with cations or bases and, in the contextof this invention, are understood to be salts formed by at least onecompound used in accordance with the invention—normally an acid(deprotonated)—such as an anion, particularly when used on humans and/ormammals. These physiologically acceptable salts may also be formed withanions or acids and, in the context of this invention, are understood asbeing salts formed by at least one compound used in accordance with theinvention—normally protonated, for example in nitrogen—such as a cationand at least one physiologically tolerated anion, particularly when usedon humans and/or mammals. This definition specifically includes in thecontext of this invention a salt formed by a physiologically toleratedacid, i.e. salts of a specific active compound with physiologicallytolerated organic or inorganic acids—particularly when used on humansand/or mammals. Examples of this type of salts are those formed with:hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonicacid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid,tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The term “solvate” in accordance with this invention should beunderstood as meaning any form of the active compound in accordance withthe invention in which said compound is bonded by a non-covalent bond toanother molecule (normally a polar solvent), including especiallyhydrates and alcoholates, like for example, methanolate. A preferredsolvate is the hydrate.

Any compound that is a prodrug of a compound of formula (I) is alsowithin the scope of the invention. The term “prodrug” is used in itsbroadest sense and encompasses those derivatives that are converted invivo to the compounds of the invention. Examples of prodrugs include,but are not limited to, derivatives and metabolites of the compounds offormula I that include biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Preferably, prodrugs of compounds with carboxylfunctional groups are the lower alkyl esters of the carboxylic acid. Thecarboxylate esters are conveniently formed by esterifying any of thecarboxylic acid moieties present on the molecule. Prodrugs can typicallybe prepared using well-known methods, such as those described by Burger“Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed.,2001, Wiley), “Design and Applications of Prodrugs” (H. Bundgaard ed.,1985, Harwood Academic Publishers) and Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (April 2002).

The compounds of the present invention represented by the abovedescribed formula (I) may include enantiomers depending on the presenceof chiral centres or isomers depending on the presence of multiple bonds(e.g. Z, E). The single isomers, enantiomers or diastereoisomers andmixtures thereof fall within the scope of the present invention.

Furthermore, any compound referred to herein may exist as tautomers.Specifically, the term tautomer refers to one of two or more structuralisomers of a compound that exist in equilibrium and are readilyconverted from one isomeric form to another. Common tautomeric pairs areamine-imine, amide-imidic acid, keto-enol, lactam-lactim, etc.

Unless otherwise stated, the compounds of the invention are also meantto include isotopically-labelled forms i.e. compounds which differ onlyin the presence of one or more isotopically-enriched atoms. For example,compounds having the present structures except for the replacement of atleast one hydrogen atom by a deuterium or tritium, or the replacement ofat least one carbon by ¹³C- or ¹⁴C-enriched carbon, or the replacementof at least one nitrogen by ¹⁵N-enriched nitrogen are within the scopeof this invention.

The compounds of formula (I), or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I), or of its salts, solvates or prodrugs.

As noted previously, the term “pharmaceutically acceptable salts,solvates, prodrugs” refers to any salt, solvate, or any other compoundwhich, upon administration to the recipient is capable of providing(directly or indirectly) a compound as described herein. However, itwill be appreciated that non-pharmaceutically acceptable salts, solvatesand prodrugs also fall within the scope of the invention since those maybe useful in the preparation of pharmaceutically acceptable salts,solvates and prodrugs. The preparation of salts, solvates and prodrugscan be carried out by methods known in the art.

As used herein, the terms “treat”, “treating” and “treatment” includethe eradication, removal, reversion, alleviation, modification, orcontrol of a disease or condition, such as pain.

As used herein, the terms “prevention”, “preventing”, “preventive”,“prevent” and “prophylaxis” refer to the capacity of a compound offormula (I) to avoid, minimize or difficult the onset or development ofa disease or condition, such as pain, before its onset.

Therefore, by “treating” or “treatment” and/or “preventing” or“prevention”, as a whole, is meant at least a suppression or anamelioration of the symptoms associated with the condition afflictingthe subject, where suppression and amelioration are used in a broadsense to refer to at least a reduction in the magnitude of a parameter,e.g., symptom associated with the condition being treated, such as pain.As such, the method of the present invention also includes situationswhere the condition is completely inhibited, e.g., prevented fromhappening, or stopped, e.g., terminated, such that the subject no longerexperiences the condition. As such, the present method includes bothpreventing and managing pain, particularly, neuropathic pain, such ashyperalgesia or allodynia.

As used herein, the term “potentiating the analgesic effect of an opioidor opiate” refer to the increase in the affectivity of the analgesiceffect of said opioids or opiates produced by compounds of formula (I).In an embodiment of the invention said potentiating effect induces anincrease in the analgesic effect of opioids by a factor of 1.2, 1.5, 2,3, 4 or more, even in some case by a factor of 14 or 15, when compared,with the opioids or opiates, or with the compound of formula (I) whenadministered in isolation. The measurement can be done following anyknown method in the art. In an embodiment of the invention, the compoundof formula (I) potentiates the analgesic effect of an opioid or opiateby a factor of at least 1.2 when measured in a mechanical allodynia ratmodel or in a in a thermal hyperalgesia rat model. In a furtherembodiment, said factor is of at least 1.5, 2, 3, 4 or more, even insome case by a factor of 14 or 15.

In the compounds of formula (I) or subgroups thereof, the substituent R¹and R² may be bonded to any carbon atom of the corresponding ring.Therefore, in the compounds of formula (I) or subgroups thereof, thesubstituent R¹ may be bonded to any carbon of the morpholinone ring, forexample, the substituent R¹ may be bonded to any one of carbons 2, 5 or6, as depicted hereinafter:

Likewise, in the compounds of formula (I) or subgroups thereof, thesubstituent R² may be bonded to any carbon atom of the naphthyl or the5,6-dihydronaphthalenyl ring, for example, the substituent R² may bebonded to any one of carbon atoms 1, 3, 4, 5, 6, 7, or 8, as depictedhereafter:

In a particular variant of the invention, the dashed line (representedby represents a double bond in the formula (I) or subgroups thereof.

In a particular embodiment, n and m are 0, i.e., the compound of formula(I) is 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one.

In another embodiment, R¹ is hydroxy.

In another embodiment, R² is substituted or unsubstituted alkyl,preferably C₁₋₄alkyl, and more preferably methyl. If substituted, alkylis preferably substituted with hydroxy. Accordingly, hydroxymethyl is apreferred radical.

In another embodiment, R² is C₁₋₆alkoxy, preferably C₁₋₄alkoxy, and morepreferably methoxy.

According to a particular embodiment, halogen is preferably, bromo orfluoro more preferably as R² in the compounds of the invention.

In additional preferred embodiments, the preferences described above forthe different substituent are combined. The present invention is alsodirected to such combinations of preferred substitutions in the formulaeabove.

Particular individual compounds of the invention falling under formula(I) include the compounds listed below:

-   4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(8-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(6-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(7-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   6-hydroxy-4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(5,6-dimethoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(6-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(6-bromonaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(5-methyl-1-(6-methylnaphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(6-(hydroxymethyl)naphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(4-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   4-(2-(1-(5,6-dihydroxy-5,6-dihydronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one-   or a pharmaceutically acceptable salt, isomer, prodrug or solvate    thereof.

The compounds of formula (I) defined above can be obtained by availablesynthetic procedures. For example, they can be prepared by reacting acompound of formula (II):

in which R² and n are as defined above in formula (I), and X is aleaving group, preferably chlorine or pyridinium, with a compound offormula (III):

in which R¹ and m are as defined above in formula (I).

The reaction of compounds of formulas (II) and (III) is preferablycarried out in an aprotic solvent, but not limited to, such asdimethylformamide (DMF) in the presence of an inorganic base, such asK₂CO₃. Compounds of formula (III) are commercially available or can beprepared by conventional methods.

The obtained compounds, when necessary, can be collected from thereaction mixture according to the methods known in the art. For example,when insoluble materials are present, the desired compound can beobtained—after removing the insoluble materials by filtration—byremoving the solvent, e.g. by removing the solvent under reducedpressure, and/or by adding water to the residue and extracting themixture with a water-immiscible organic solvent such as ethyl acetate,etc. Optionally, the desired compound can be obtained after drying overanhydrous sodium sulfate, for instance, and further, if necessary, bypurifying with any conventional method, such as recrystallization,column chromatography, or other techniques.

It is evident that in the foregoing and in the exemplified reactions,the reaction products may be isolated from the reaction medium and, ifnecessary, further purified by methods generally known in the art, suchas extraction, crystallization, trituration and chromatography. Wherethe above described processes for the preparation of compounds of theinvention give rise to mixtures of stereoisomers, these isomers may beseparated by conventional techniques such as preparative chromatography.If there are chiral centers the compounds may be prepared in racemicform, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution.

Many compounds comprised by formula (I) may be converted into each otherfollowing functional group transformation reactions well known in theart. Preferably, they are obtained by utilizing suitable startingmaterials, like for example, compounds of formula (II) and (III)including already the desired substituents.

In particular, in those compounds with hydroxy substitutents as R¹ orR², such hydroxy moieties may be converted into the corresponding C₁₋₆alkoxy by reacting the compounds with an C₁₋₆alkyl halide in thepresence of a base, such as an alkali of alkaline metal hydride, likelithium hydride or sodium hydride, or an alkali metal alkoxide, likesodium or potassium methoxide or ethoxide, potassium tert-butoxide, orpotassium carbonate, triethylamine, pyridine, sodium iodide, cesiumcarbonate, etc. The C₁₋₆alkyl halide may be selected, for instance, frommethyl or ethyl iodide.

In addition, in those compounds with C₁₋₆alkoxy substitutents as R¹ orR², such C₁₋₆alkoxy moieties may be converted into the correspondinghydroxy by submitting the relevant compounds to acidic conditions, suchas with hydrochloric acid, hydrobromic acid, or hydroiodic acid.

It has been found that the compounds of general formula (I) are usefulin the treatment of pain. In a particular embodiment of the presentinvention, the pain is neuropathic pain. More preferably, the pain ishyperalgesia or allodynia.

The present invention further provides medicaments or pharmaceuticalcompositions comprising a compound of this invention, or apharmaceutically salt, derivative, prodrug or stereoisomer thereoftogether with a pharmaceutically acceptable carrier, adjuvant, orvehicle, for administration to a patient.

The auxiliary materials or additives of a pharmaceutical compositionaccording to the present invention can be selected among carriers,excipients, support materials, lubricants, fillers, solvents, diluents,colorants, flavour conditioners such as sugars, antioxidants, binders,adhesives, disintegrants, anti-adherents, glidants and/or agglutinants.In the case of suppositories, this may imply waxes or fatty acid estersor preservatives, emulsifiers and/or carriers for parenteralapplication. The selection of these auxiliary materials and/or additivesand the amounts to be used will depend on the form of application of thepharmaceutical composition.

The medicament or pharmaceutical composition according to the presentinvention may be in any form suitable for the application to humansand/or animals, preferably humans including infants, children and adultsand can be produced by standard procedures known to those skilled in theart. Therefore, the formulation in accordance with the invention may beadapted for topical or systemic application, particularly for dermal,transdermal, subcutaneous, intramuscular, intra-articular,intraperitoneal, intravenous, intra-arterial, intravesical,intraosseous, intracavernosal, pulmonary, buccal, sublingual, ocular,intravitreal, intranasal, percutaneous, rectal, vaginal, oral, epidural,intrathecal, intraventricular, intracerebral, intracerebroventricular,intracisternal, intraspinal, perispinal, intracranial, delivery vianeedles or catheters with or without pump devices, or other applicationroutes.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, pills, caplets, gel caps, chewing gums,capsules, granules, drops, syrups or solutions and may containconventional excipients known in the art such as binding agents, forexample syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions orreconstitutable dry preparations, aerosols or sprays in the appropriateunit dosage form. Adequate excipients can be used, such as bulkingagents, buffering agents or surfactants.

The composition of the invention may be formulated as deposits indissolved form or in patches, for percutaneous application.

Skin applications include ointments, gels, creams, lotions, suspensionsor emulsions.

Suitable form of rectal application is by means of suppositories.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

In one embodiment of the invention it is preferred that compound offormula (I) is used in therapeutically effective amounts. The physicianwill determine the dosage of the present therapeutic agents which willbe most suitable and it will vary with the form of administration andthe particular compound chosen, and furthermore, it will vary with thepatient under treatment, the age of the patient, the type of disease orcondition being treated. When the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. The compounds areuseful in the same manner as comparable therapeutic agents and thedosage level is of the same order of magnitude as is generally employedwith these other therapeutic agents. Active compounds will typically beadministered once or more times a day for example 1, 2, 3 or 4 timesdaily, with typical total daily doses in the range of from 0.1 to 1000mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

Particularly, the combination of at least one compound of formula (I)and at least one opioid or opiate may be formulated for itssimultaneous, separate or sequential administration, with at least apharmaceutically acceptable carrier, additive, adjuvant or vehicle. Thishas the implication that the combination of the compound of formula (I)and the opioid or opiate may be administered:

-   -   a) As a combination that is being part of the same medicament        formulation, both being then administered always simultaneously.    -   b) As a combination of two units, each with one of them giving        rise to the possibility of simultaneous, sequential or separate        administration. In a particular embodiment, the compound of        formula (I) is independently administered from the opioid or        opiate (i.e in two units) but at the same time. In another        particular embodiment, the compound of formula (I) is        administered first, and then the opioid or opiate is separately        or sequentially administered. In yet another particular        embodiment, the opioid or opiate is administered first, and then        the compound of formula (I) is administered, separately or        sequentially, as defined.

As noted above, a compound of formula (I), or a pharmaceuticallyacceptable salt, isomer, prodrug or solvate thereof, is useful forpotentiating the analgesic effects of an opioid or opiate.

According to the present invention the dosage of the opioid or opiatecan be reduced when combined with a compound of formula (I), andtherefore attaining the same analgesic effect with a reduced dosage. Thecompounds of formula (I) may induce an increase in the analgesic effectof opioids of a factor of 1.2, 1.5, 2, 3, 4 or more, even in some caseby a factor of 14 or 15.

A preferred embodiment of the present invention comprises the use of acombination of4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-oneand morphine or tramadol. In a preferred embodiment of the presentinvention, the opiate utilized is morphine or its analogs. In anotherpreferred embodiment of the present invention, the opioid utilized istramadol or its analogs.

The following examples are merely illustrative of certain embodiments ofthe invention and cannot be considered as restricting it in any way.

EXAMPLES Example N^(o) 1 Synthesis of4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one

To a stirred suspension of sodium hydride (65 mg 60% dispersion inmineral oil, 1.63 mmol) in DMF (3 ml), cooled to 0-5° C., a solution ofmorpholin-3-one (91 mg, 0.91 mmol) in DMF (3 ml) was added dropwise. Themixture was stirred at room temperature for 3 hrs. Then, a solution of3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0.7mmol) in DMF (4 ml) was added and the mixture was heated to 50° C. for14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise,and it was evaporated to dryness in vacuum. The resulting residue waspartitioned between dichloromethane and water. The organic layer waswashed with water, dried over Na₂SO₄, filtered and evaporated giving 223mg of crude residue, which was purified by a silica gel columnchromatography (eluent: ethyl acetate) and4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one(192 mg, 78%) was obtained as an amorphous white solid.

Purity determined by HPLC: 100%

¹H-NMR (CDCl₃) δ ppm: 7.95-7.8 (m, 4H), 7.6-7.5 (m, 3H), 5.7 (s, 1H),4.45 (t, J=5.2 Hz, 2H), 4.2 (s, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.8 (t,J=5.3 Hz, 2H), 3.6 (t, J=5.4 Hz, 2H), 2.35 (s, 3H).

Pharmacological Data

Effect on Capsaicin in Development of Mechanical Allodynia

This model uses the von-Frey Filaments and is a model to test theeffects or symptoms of neuropathic pain, allodynia etc.

Interest of the model:

-   -   The injection of 1 μg of capsaicin to experimental animals        produces acute pain followed by hyperalgesia/allodynia    -   The mechanisms involved in capsaicin-induced acute pain and        hyperalgesia are relatively well known (mainly activation of        peripheral nociceptors and sensitization of spinal cord neurons,        respectively)

FIG. 1 shows the test protocol for all tests with von Frey filaments.After habituation mice were according to FIG. 1 first treated with thetest-compound (or solvent in controls). Then 1 μg capsaicin (1% DMSO) isinjected into their paw resulting in developing pain in the effectedpaw. The effected paw is then treated with a mechanical stimulus and thelatency time before the paw is withdrawn is measured.

This pharmacological test showed the effect of the compound of example 1in the model described. As shown in FIG. 2 there is a dose dependency ofthe treatment with the compound of example 1 showing analgesia incapsaicin-induced neuropathic pain.

Effects of Example N^(o) 1 in the Tail-Flick Test in Mice Modulation ofMorphine Analgesia Materials and Methods Animals

Male CD1 wild type mice were purchased from Charles-River (France).Animals were housed in groups of ten, provided with food and water adlibitum and kept in controlled laboratory conditions with thetemperature maintained at 21±1° C. and light in 12-hour light/darkcycles (on at 07:00 am and off at 07:00 pm). Animals from 6 to 8 weeksold were used. Experiments were carried out between 9:00 am and 15:00 pmin a soundproof, air-regulated experimental room. All experimentalprocedures and animal husbandry were conducted according to ethicalprinciples for the evaluation of pain in conscious animals (Zimmermann,1983) and to the European Communities Council Directive of 24 Nov. 1986(86/609/ECC). The experimental work was approved by the local EthicalCommittee.

Drugs

The following drugs were used: Example n^(o) 1 (synthesized byLaboratorios Dr. Esteve S. A., Spain) and morphine hydrochloride(provided by Agenda Española de medicamentos y productos sanitarios,Area Estupefacientes). Drugs were dissolved in (hydroxypropyl)methylcellulose (HPMC, 0.5%) (H9262, Sigma-Aldrich). Morphine was administeredin a volume of 5 ml/kg of body weight through the subcutaneous (s.c.)and Example n^(o) 1 was administered in a volume of 10 ml/kg of bodyweight through the intraperitoneal route (i.p.). The doses of drugsrefer to their salt forms.

Nociceptive Assay Tail-Flick Test

The test was performed as previously described (Moncada et al., 2003).Briefly, the animals were restrained in a Plexiglas tube and placed onthe tail-flick apparatus (Panlab, LE 7106, Spain). A noxious beam oflight was focussed on the tail about 3 cm from the tip, and thetail-flick latency (TFL, latency or tail removal from the radiant heatsource) was recorded automatically to the nearest 0.1 s. The intensityof the radiant heat source was adjusted to yield baseline latenciesbetween 2 and 4 s. A cut-off time was set at 10 s to avoid heat-relateddamage. The animals received two injections at the same time: HPMC(i.p.)+HPMC (s.c.), HPMC (i.p.)+morphine (2 mg/kg, s.c.), Example n^(o)1 (5, 10, 20 mg/kg, i.p.)+HPMC (s.c.), or Example n^(o) 1 (5, 10, 20mg/kg, i.p.)+(2 mg/kg, s.c.), and tail flick latencies were measured 30min post-administration. All experiments were performed under blindconditions.

Data and Statistical Analysis

Data were expressed as means±S.E.M of the tail flick latency in seconds(s). In order to generate dose-response curves, data were also convertedto % Analgesia. By comparison with the mean of vehicle treated group(defined as 0% Analgesia) and the cut-off (prefixed at 10 s) (defined as100% Analgesia) individual percentages of Analgesia were determined bythe formula:% Analgesia=[(Test Latency−Vehicle Latency)/(Cutoff Latency−VehicleLatency)]×100

“Example n^(o) 1+morphine” treatment groups were compared with “Examplen^(o) 1+vehicle” groups using two-way ANOVA followed by Bonferronipost-hoc test. Statistical analyses were performed with GraphPad Prismversion 4 program (GraphPad software, San Diego, Calif.). Statisticalsignificance was set at the 95% confidence level (two tailed) (*p<0.05,**p<0.01, ***p<0.001). N=8-12 animals/group.

Results

As shown in FIG. 3, Example n^(o) 1 enhances the analgesic effect of afixed dose of morphine in the tail-flick test in mice.

The invention claimed is:
 1. A compound of the formula (I)

wherein R¹ and R² are independently selected from the group consistingof substituted or unsubstituted C₁₋₆alkyl, halogen, hydroxy andC₁₋₆alkoxy; n and m are independently selected from 0, 1, and 2; thedashed line (represented by - - - - - ) represents an optional doublebond or a pharmaceutically acceptable salt, isomer, prodrug or solvatethereof.
 2. The compound according to claim 1, wherein the dashed line(represented by - - - - - ) represents a double bond.
 3. The compoundaccording to claim 1, wherein R¹ is hydroxy.
 4. The compound accordingto claim 1, wherein R² is substituted or unsubstituted C₁₋₄alkyl,preferably methyl or hydroxymethyl.
 5. The compound according to claim1, wherein R² is C₁₋₄alkoxy, preferably methoxy.
 6. The compoundaccording to claim 1, wherein R² is bromo or fluoro.
 7. The compoundaccording to claim 1, wherein said compound is:4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(8-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(7-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;6-hydroxy-4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(5,6-dimethoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-bromonaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(5-methyl-1-(6-methylnaphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-(hydroxymethyl)naphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(4-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;or4-(2-(1-(5,6-dihydroxy-5,6-dihydronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;or a pharmaceutically acceptable salt, isomer, prodrug or solvatethereof.
 8. A combination for simultaneous, separate or sequentialadministration comprising at least one compound of formula (I) asdefined in claim 1, or a pharmaceutically acceptable salt, isomer,prodrug or solvate thereof, and at least one opioid or opiate.
 9. Aprocess for the preparation of a compound of formula (I) as defined inclaim 1 or a pharmaceutically acceptable salt, isomer, prodrug orsolvate thereof, which comprises reacting a compound of formula (II):

in which R² and n are as defined above in formula (I), and X is aleaving group, preferably chlorine or pyridinium, with a compound offormula (III):

in which R¹ and m are as defined above in formula (I).
 10. Apharmaceutical composition comprising at least one compound of formula(I) as defined in any of claim 1, or a pharmaceutically acceptable salt,isomer, prodrug or solvate thereof and a pharmaceutically acceptablecarrier, adjuvant or vehicle.
 11. The compound according to claim 4,wherein R² is methyl or hydroxymethyl.
 12. The compound according toclaim 5, wherein R² is methoxy.
 13. The combination according to claim8, wherein the at least one compound of formula (I) comprises one of thefollowing conditions (a) to (e): (a) the dashed line (representedby - - - - - ) represents a double bond; (b) R¹ is hydroxyl; (c) R² issubstituted or unsubstituted (d) R² is C₁₋₄alkoxy; and (e) R² is bromoor fluoro.
 14. The combination according to claim 8, wherein the atleast one compound of formula (I) is:4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(8-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(7-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(7-hydroxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;6-hydroxy-4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(5,6-dimethoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-methoxynaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-bromonaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(5-methyl-1-(6-methylnaphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(6-(hydroxymethyl)naphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;4-(2-(1-(4-fluoronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;or4-(2-(1-(5,6-dihydroxy-5,6-dihydronaphthalen-2-yl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one;or a pharmaceutically acceptable salt, isomer, prodrug or solvatethereof.
 15. The process according to claim 9, wherein the leaving groupis chlorine or pyridinium.
 16. A method for the treatment of pain, themethod comprising administering to a subject in need of such a treatmenta therapeutically effective amount of a compound of formula (I) asdefined in claim
 1. 17. The method according to claim 16, wherein thepain is selected from the group consisting of neuropathic pain,inflammatory pain and other pain conditions involving allodynia and/orhyperalgesia.
 18. The method according to claim 16, wherein the compoundof formula (I) potentiates the analgesic effects of an opioid or opiate.19. The method according to claim 18, wherein the opioid is morphine.